switching therapy from intravenous landiolol to … increased β-adrenergic tone in hyperthyroidism...

2603

doi: 10.2169/internalmedicine.8846-17

Intern Med 56: 2603-2609, 2017

http://internmed.jp

【 CASE REPORT 】

Switching Therapy from Intravenous Landiolol toTransdermal Bisoprolol in a Patient with Thyroid Storm

Complicated by Decompensated Heart Failure andGastrointestinal Dysfunction

Shigeo Godo 1,2, Yu Kawazoe 2, Hiroshi Ozaki 3, Motoo Fujita 2, Daisuke Kudo 2,4,

Ryosuke Nomura 2, Hiroaki Shimokawa 1 and Shigeki Kushimoto 2,4

Abstract:Thyroid storm is a life-threatening disorder that remains a therapeutic challenge. Although β-blockers are

the mainstay for treatment, their use can be challenging in cases complicated by rapid atrial fibrillation and

decompensated heart failure. We present a case of thyroid storm-associated atrial fibrillation and decompen-

sated heart failure complicated by gastrointestinal dysfunction secondary to diffuse peritonitis that was suc-

cessfully managed by a switching therapy, in which the continuous intravenous administration of landiolol

was changed to bisoprolol via transdermal patch, in the acute phase treatment. This switching therapy may

offer a promising therapeutic option for this potentially lethal disorder.

Key words: acute heart failure, atrial fibrillation, bisoprolol transdermal patch, critical care, landiolol, thyroid

storm

(Intern Med 56: 2603-2609, 2017)(DOI: 10.2169/internalmedicine.8846-17)

Introduction

Thyroid storm is a potentially lethal disease characterized

by multiple organ dysfunction secondary to thyrotoxicosis in

which rapid atrial fibrillation and acute heart failure are fre-

quent complications (1, 2). β-blockers are a drug of choice

for the treatment of the cardiovascular symptoms induced by

the increased β-adrenergic tone in hyperthyroidism (1, 3, 4).

Although the immediate administration of relatively high

doses of β-blockers is required to achieve adequate control

of profound tachycardia in the setting of thyroid storm, their

use can be challenging especially in cases of thyroid storm

complicated by decompensated heart failure, and in cases in-

volving patients who cannot tolerate oral medications due to

gastrointestinal dysfunction, which is a common manifesta-

tion of thyroid storm (4). This is due to the potential for

conventional intravenous β-blockers (e.g. propranolol) to

further exacerbate the heart failure or to induce the circula-

tory collapse of a failing heart (5). Moreover, no specific

treatment of acute congestive heart failure in patients with

thyroid storm is available, even in the latest guidelines for

the management of thyroid storm (4, 6). Recently, novel

forms of cardio-selective β1-blockers have become available

in Japan, including the world’s first transdermal patch of the

selective β1 blocker bisoprolol (BisonoⓇ Tape, Toa Eiyo, To-

kyo, Japan) and an ultra-short-acting selective β1 blocker

landiolol (OnoactⓇ for Intravenous Infusion, Ono Pharma-

ceutical, Osaka, Japan), which is used for the treatment of

tachyarrhythmia (atrial fibrillation and atrial flutter) in pa-

tients with left ventricular dysfunction (7). However, the

usefulness of these new drugs in the treatment of thyroid

storm remains largely unknown because only a few case re-

ports are available (8, 9).

We herein present the case of a patient with thyroid

storm-associated atrial fibrillation and decompensated heart

１Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan, ２Department of Emergency and Critical Care

Medicine, Tohoku University Hospital, Japan, ３Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate

School of Medicine, Japan and ４Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Japan

Received: January 10, 2017; Accepted: February 20, 2017; Advance Publication by J-STAGE: September 6, 2017

Correspondence to Dr. Shigeo Godo, [email protected]

Intern Med 56: 2603-2609, 2017 DOI: 10.2169/internalmedicine.8846-17

2604

failure complicated by gastrointestinal dysfunction due to

duodenal ulcer perforation that was successfully managed by

a switching therapy from intravenous landiolol to transder-

mal bisoprolol.

Case Report

A 30-year-old woman who had no past medical history

was referred to our department for the treatment of thyroid

storm with concomitant multiple organ failure and a perfo-

rated duodenal ulcer. One month prior to her presentation,

she exhibited weight loss (from 70 to 60 kg) despite an ex-

cessive appetite. One week before her presentation, she

complained of dyspnea and palpitation on effort and gener-

alized edema. Twelve hours before her presentation, she ex-

perienced a sudden onset of severe upper abdominal pain

and the worsening of dyspnea and palpitation. This led her

to be transferred to another hospital during the night, where

she arrived with modest delirium, jaundice, anasarca, ortho-

pnea, severe hypotension and atrial fibrillation with a rapid

ventricular response (systolic blood pressure, 70 mmHg;

pulse 200 beats/min) (Fig. 1A). A chest X-ray showed

marked cardiomegaly with bilateral pleural effusions that

were larger on the right side (Fig. 2A). Contrast-enhanced

computed tomography showed large amounts of free air in

front of the edematous duodenal wall and ascites around the

liver (Fig. 2B). She was diagnosed with diffuse peritonitis

secondary to duodenal perforation and underwent an emer-

gency operation. On the second morning (12 hours after her

arrival), the laboratory data revealed hyperthyroidism associ-

ated with multiple organ dysfunction including cardiac dys-

function, hepatic failure with jaundice, and acute kidney in-

jury (Table). The Burch and Wartofsky diagnostic score

reached 95 points, leading to the diagnosis of thyroid

storm (4, 10). On presentation to our institution, she showed

modest delirium, jaundice, diffuse goiter, obvious anasarca

with moist and warm skin, with the following findings:

blood pressure, 71/53 mmHg; pulse, 113 beats/min (atrial

fibrillation); body temperature, 37.5℃ and oxygen saturation

96% under mechanical ventilation with an inspired oxygen

fraction of 0.4 and a positive end expiratory pressure of 5

cmH2O. Her height, weight and body mass index were 157

cm, 75.1 kg, and 30.5 kg/m2, respectively. Echocardiography

revealed mild systolic dysfunction with a left ventricular

ejection fraction of 40-45%. Acute coronary syndrome and

myocarditis were ruled out based on the negative findings of

emergency coronary angiography and an endomyocardial bi-

opsy. The patient’s hemodynamic parameters were as fol-

lows: mean pulmonary capillary wedge pressure, 18 mmHg;

pulmonary artery pressure, 42/26 mmHg (mean, 31 mmHg);

mean right atrial pressure, 24 mmHg; cardiac index, 3.9 L/

min/m2; systemic vascular resistance index, 208 dyn·sec/cm5/

m2; and pulmonary vascular resistance index, 93 dyn·sec/

cm5/m2, which were compatible with high output cardiac

failure with extremely low systemic vascular resistance in

thyroid storm (11). Based on these clinical data, our initial

therapy included antithyroid therapy with intravenous thia-

mazole (40 mg/day) and hydrocortisone (200 mg/day), con-

tinuous renal replacement therapy for the continuous pro-

gression of metabolic acidosis, dobutamine (3 μg/kg/min),

noradrenaline (0.4 μg/kg/min), vasopressin (3 units/h) and

an intra-aortic balloon pump in order to maintain a mean ar-

terial pressure of at least 65 mmHg (Fig. 3). Although she

presented with decompensated heart failure and hemody-

namic instability, her rapid atrial fibrillation was refractory

to rhythm control treatment using direct current; her atrial

fibrillation recurred promptly after a temporal termination by

direct current. We therefore adopted a rate control strategy

in which landiolol was administered under the close moni-

toring of the patient’s hemodynamic status at an initial dose

of 1 μg/kg/min. The dose was then up-titrated by 1 μg/kg/

min every hour to a maximum dose of 17 μg/kg/min in or-

der to achieve a target heart rate of <130 beats/

min (4, 7, 12) (Fig. 1B and C, 3). As expected, the control

of tachycardia led to a significant improvement in the car-

diac function and hemodynamics (Fig. 3). On day 3, after

her hemodynamic status had improved, we administered a

bisoprolol transdermal patch (initial dose: 4 mg/day). The

dose was subsequently increased to 8 mg/day while landi-

olol was successfully tapered off by day 6 (Fig. 3). This

switching therapy was well-tolerated without an exacerba-

tion of the patient’s heart failure. On day 8, she underwent

an emergency re-operation due to suture failure at the site of

the perforated duodenal ulcer. However, she was able to

continue the steady β-blocker treatment and did not suffer

from a relapse of thyroid storm due to this invasive proce-

dure. Because mild hypotension that was dependent on a

low dose of noradrenaline persisted, we added a non-

selective β-blocker, propranolol, in order to reverse the re-

duced systemic vascular resistance, which was possibly due

to thyroid hormone-induced β2 receptor upregulation in the

vascular periphery (13). The additional propranolol allowed

for noradrenaline to be tapered off within two weeks. On

day 19, she had a spontaneous return to sinus rhythm and

her cardiac functions normalized; she was therefore dis-

charged from the intensive care unit (Fig. 2C, Table). On

day 99, she was discharged from the hospital after long-term

rehabilitation for generalized muscle weakness due to thy-

roid myopathy.

Discussion

The present case highlighted two important clinical impli-

cations. First, switching therapy from intravenous landiolol

to transdermal bisoprolol is feasible and effective in the

management of thyroid storm-associated atrial fibrillation

and decompensated heart failure, even when such cases are

complicated by gastrointestinal dysfunction. Second, the tol-

erability of the initial treatment with landiolol helps to pre-

dict a durable dosage in the subsequent treatment with con-

ventional β-blockers, the induction of which otherwise has

the potential to further exacerbate heart failure. To the best


2605

Figure　1.　Electrocardiography. (A) The electrocardiogram on the initial presentation to the previ-ous hospital before the administration of landiolol showed excessively rapid atrial fibrillation (180-200 beats/min). (B) The electrocardiogram on her presentation to our department under the intrave-nous administration of landiolol (5 μg/kg/min) showed a rapid atrial fibrillation (130-160 beats/min). (C) The electrocardiogram under the intravenous administration of landiolol at a maximum dose of 17 μg/kg/min showed the successful control of atrial fibrillation (90-110 beats/min).

B

C

A

of our knowledge, this is the first case report to demonstrate

a successful switching therapy from intravenous landiolol to

transdermal bisoprolol in a patient with thyroid storm-

associated decompensated heart failure complicated by gas-

trointestinal dysfunction.

First, the switching therapy from intravenous landiolol to

transdermal bisoprolol offers a safe and effective strategy for

managing thyroid storm-associated atrial fibrillation with

acute heart failure, even when the gastrointestinal function is

compromised. β-blockers are the mainstay treatment for

managing rapid thyroid storm-associated atrial fibrilla-

tion (1, 3, 4). Although the bisoprolol transdermal patch had

yet to be approved for the treatment of tachyarrhythmia

(such as rapid atrial fibrillation) we used the transdermal

patch, instead of oral bisoprolol due to concerns regarding

the possibility of poor intestinal absorption in the acute set-


2606

Figure　2.　Chest X-rays films and contrast-enhanced computed tomography. (A) The chest X-ray on presentation to previous hospital showed marked cardiomegaly with bilateral pleural effusions that were larger on the right side. (B) Contrast-enhanced computed tomography on presentation to the previous hospital (before surgery) revealed free air in the peritoneal cavity with edematous duode-num and ascites. (C) The chest X-ray on discharge from the intensive care unit showed a marked improvement of heart failure.

A CB

Table.　Laboratory Data.

Reference range On admission On discharge from ICU

Thyroid function tests

TSH (μIU/mL) 0.35-4.94 <0.01 <0.01

fT3 (pg/mL) 1.71-3.71 6.16 1.15

fT4 (ng/dL) 0.70-1.48 2.98 0.43

Tg (ng/mL) 0-33.7 348 NA

TSAb (%) 0-120 842 NA

TgAb (IU/mL) 0-28.0 98.6 NA

TPOAb (IU/mL) 0-16.0 201 NA

Others

WBC (/μL) 3,500-9,100 17,600 15,200

T-bil (mg/dL) 0.3-1.2 13.4 6.5

D-bil (mg/dL) 0-0.4 10.3 3.9

AST (IU/L) 10-40 46 24

ALT (IU/L) 5-40 54 42

BUN (mg/dL) 8.0-22.0 17.0 10.0

Cre (mg/dL) 0.47-0.79 0.30 0.19

BNP (pg/mL) <18.4 986 493

CRP (mg/dL) <0.30 3.6 0.9

Alb (mg/dL) 3.8-5.2 2.3 1.3

T-chol (mg/dL) 150-219 <39 66

Lactate (mmol/L) 0.37-1.65 3.3 1.2

Alb: albumin, ALT: alanine-aminotransferase, AST: aspartate-aminotransferase, BNP: brain natri-

uretic peptide, BUN: blood urea nitrogen, Cre: creatinine, CRP: C-reactive protein, D-bil: direct

bilirubin, fT3: free triiodothyronine, fT4: free thyroxine, ICU: intensive care unit, NA: not avail-

able, T-bil: total bilirubin, T-chol: total cholesterol, Tg: thyroglobulin, TgAb: thyroglobulin anti-

body, TPOAb: thyroid peroxidase antibody, TSAb: thyroid stimulating antibody, TSH: thyroid-

stimulating hormone, WBC: white blood cell

ting of heart failure complicated by gastrointestinal dysfunc-

tion due to diffuse peritonitis secondary to duodenal ulcer

perforation. In critically ill patients, enteral administration

can be hampered by concurrent gastrointestinal dysfunction,

including vomiting, diarrhea, gastroparesis, and ileus, lead-

ing to poor tolerance of enteral feeding. This is also the case

in patients with thyroid storm, where gastrointestinal dys-

function is such a common manifestation that it is included

in the diagnostic criteria for thyroid storm (10). In compari-

son to a 5 mg oral bisoprolol formulation, an 8 mg bi-

soprolol transdermal patch results in lower peak and higher

trough concentrations of bisoprolol while exerting similar

blood pressure and heart rate lowering effects. The transder-

mal patch provides a stable treatment with bisoprolol via


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Figure　3.　The clinical course of the hemodynamic status, circulatory management, and thyroid hormone levels. Each arrow indicates an emergency operation. Bis tape: bisoprolol transdermal patch, BW: body weight, CAs: catecholamines, CRRT: continuous renal replacement therapy, fT3: free triiodothyronine, fT4: free thyroxine, HR: heart rate, IABP: intra-aortic balloon pump, Land: landiolol, LVEF: left ventricular ejection fraction, MMI: thiamazole, PPL: propranolol, sBP: systolic blood pressure, TSH: thyroid-stimulating hormone

IABPCRRTCAsMMIPPL

LandBis tape

HRsBPLVEF

TSHfT3fT4

BW

8 (mg/day)

4

40 30 20

1710 4 (μg/kg/min)

30

1 2 3 4 5 6 7 8 9 10 11 12

40

80

120

160

200

25

50

75

100

125

150

HR(b

pm)

LVEF

(%),

sBP

(mm

Hg)

1 2 3 4 5 6 7 8 9 10 11 12012345

0

2

4

6

8

TSH

(μIU

/mL)

fT3

(pg/

mL)

fT4

(ng/

dL)

1 2 3 4 5 6 7 8 9 10 11 1201,0002,0003,0004,0005,000

Day

Urin

eou

tput

(mL/

day)

556065707580

BW(k

g)

percutaneous absorption, irrespective of gastrointestinal dys-

function (14). Indeed, the novel transdermal patch of bi-

soprolol has gained increasing attention due to its emerging

usefulness in the treatment of critically ill patients. For ex-

ample, a retrospective study of 16 critically ill patients with

rapid atrial fibrillation showed that switching therapy from

landiolol to transdermal bisoprolol was successful and cost-

effective without significant adverse events (15), while a

case report on acute type B aortic dissection showed that a

control of the heart rate and blood pressure was swiftly

achieved in a stable manner using a transdermal patch of bi-

soprolol (16). Taken together, switching therapy from landi-

olol to transdermal bisoprolol after the improvement of the

systemic hemodynamic condition may offer a promising

therapeutic option for the treatment of critically ill patients,

including those with thyroid storm.

Second, the initial management of thyroid storm associ-

ated with atrial fibrillation and decompensated heart failure

using landiolol can minimize the risk of a further exacerba-

tion of heart failure, which can be induced by the acute in-

duction of treatment with conventional β-blockers. β-

blockers should be initiated with extreme care, especially for

patients with decompensated heart failure and for those with

left ventricular systolic dysfunction (5, 9). In the current

guidelines, digitalis and amiodarone are recommended for

acute rate control in patients with atrial fibrillation and left

ventricular dysfunction (17-19). However, in the present pa-

tient, digoxin and amiodarone were not only ineffective in


2608

controlling the patient’s excessive tachycardia due to atrial

fibrillation, they were also unsuitable for continuous use due

to a concurrent acute kidney injury and the potential for thy-

rotoxicosis, respectively (2, 20). Furthermore, other heart

rate lowering drugs, including verapamil and diltiazem are

contraindicated for patients with decompensated heart failure

or cardiogenic shock. Although propranolol is commonly

used in the treatment of an increased heart rate in patients

with thyrotoxicosis, the rapid administration of propranolol

is challenging in patients with thyroid storm associated with

decompensated heart failure due to the risk of cardiovascular

collapse (21). In contrast, landiolol is a novel ultra-short-

acting β-blocker with the unique properties of a short half-

life (4 minutes), easy titratability independent of renal and

hepatic clearance, a quick onset and offset of action and

high β1 receptor selectivity (β1/β2=255) (22). These advan-

tages of landiolol may allow for much safer dose adjustment

in the rate control of tachyarrhythmia in critically ill patients

in comparison to conventional drugs such as digoxin, vera-

pamil, diltiazem, and other β-blockers. Indeed, landiolol can

be titrated with the close monitoring of the hemodynamic

status in patients with atrial fibrillation and acute heart fail-

ure (7, 23). The J-Land study is a landmark trial demon-

strating the safety and efficacy of landiolol for patients with

atrial fibrillation and heart failure who show a reduced left

ventricular ejection fraction (7). In the J-Land study, 50% of

the total patients underwent switching therapy from landi-

olol (mean ± standard deviation: 6.3±3.5 μg/kg/min) to an

oral bisoprolol formulation (1.8±1.3 mg) (7). Based on the

conversion dose in the J-Land study, the therapy in the pre-

sent case could be switched from landiolol (17 μg/kg/min,

intravenously) to bisoprolol (8 mg/day, via transdermal

patch) without the exacerbation of the patient’s heart failure.

This dose corresponded to an oral bisoprolol dose of 5 mg.

Further observation and prospective trials are needed to elu-

cidate whether switching therapy can be safely conducted in

patients with more severe left ventricular systolic dysfunc-

tion (e.g. left ventricular ejection fraction <30%).

Thyroid storm remains a life-threatening disorder that can

make treatment more challenging if it is complicated by

rapid atrial fibrillation, decompensated heart failure and gas-

trointestinal dysfunction. The course of our patient provided

two important clinical issues: switching therapy from landi-

olol to transdermal bisoprolol provides a feasible manage-

ment for thyroid storm-associated atrial fibrillation with

acute heart failure, even when the gastrointestinal function is

compromised, and the initial treatment of this disorder using

landiolol can minimize the risk of a further exacerbation of

heart failure which can be induced by the acute induction of

conventional β-blockers. In conclusion, the switching ther-

apy of these drugs may be a promising therapeutic option

for patients with thyroid storm.

The authors state that they have no Conflict of Interest (COI).

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Ⓒ 2017 The Japanese Society of Internal Medicine

Intern Med 56: 2603-2609, 2017

switching therapy from intravenous landiolol to … increased β-adrenergic tone in hyperthyroidism...

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